Spontaneous conception in the presence of stage IIIC endometrioid ovarian cancer.

OBJECTIVE: To describe a rare case of spontaneous conception in a patient with a preexisting metastatic ovarian cancer. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 39-year-old Asian woman who conceived while undergoing an evaluation for primary infertility and newly detected bilateral adnexal masses. INTERVENTION(S): Staging laparotomy and total abdominal hysterectomy and bilateral salpingo-oophorectomy. MAIN OUTCOME MEASURE(S): Anatomic pathology diagnosis. RESULT(S): Blighted ovum and stage IIIC endometrioid adenocarcinoma of ovary. CONCLUSION(S): Metastatic ovarian cancer does not prevent either spontaneous ovulation or spontaneous conception.

An experimental model for the endometriosis in athymic mice.

Endometriosis is an adhesion disorder characterized by the presence of endometrial tissue in ectopic sites outside the uterus. The disease is associated with dysmenorrhea, pelvic pain and infertility. Although endometriosis is the most common gynecologic disorder, relatively little is known regarding its etiology, pathogenesis and the course of the disease. This situation is primarily due to the absence of experimental systems to examine the mechanism of endometrial cell adhesion, role of inflammatory cells and the interactions of epithelial, and stromal cells with the peritoneum and ovarian tissue leading to the development of this disorder. Dissociated human endometrial cells were suspended in peritoneal fluids of individuals with and without endometriosis and were injected into the peritoneal cavity of athymic mice. This led to development of ectopic adhesions of endometrial cells at the peritoneal and ovarian surfaces. Endometrial cells which were marked with fluorescent lipophylic dyes, prior to intraperitoneal injection, could be visualized without surgery at such sites. The studies demonstrate a model for endometriosis in athymic mice.

Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.

Women with polycystic ovary syndrome (PCOS) are insulin resistant, have insulin secretory defects, and are at high risk for glucose intolerance. We performed this study to determine the prevalence of glucose intolerance and parameters associated with risk for this in PCOS women. Two-hundred and fifty-four PCOS women, aged 14-44 yr, were prospectively evaluated at 2 centers, 1 urban and ethnically diverse (n = 110) and 1 rural and ethnically homogeneous (n = 144). The rural PCOS women were compared to 80 control women of similar weight, ethnicity, and age. A 75-g oral glucose challenge was administered after a 3-day 300-g carbohydrate diet and an overnight fast with 0 and 2 h blood samples for glucose levels. Diabetes was categorized according to WHO criteria. The prevalence of glucose intolerance was 31.1% impaired glucose intolerance (IGT) and 7.5% diabetes. In nonobese PCOS women (body mass index, <27 kg/m2), 10.3% IGT and 1.5% diabetes were found. The prevalence of glucose intolerance was significantly higher in PCOS vs. control women (chi2 = 7.0; P = 0.01; odds ratio = 2.76; 95% confidence interval = 1.23-6.57). Variables most associated with postchallenge glucose levels were fasting glucose levels (P < 0.0001), PCOS status (P = 0.002), waist/hip ratio (P = 0.01), and body mass index (P = 0.021). The American Diabetes Association criteria applied to fasting glucose significantly underdiagnosed diabetes compared to the WHO criteria (3.2% vs. 7.5%; chi2 = 4.7; P = 0.046; odds ratio = 2.48; 95% confidence interval = 1.01-6.69). We conclude that 1) PCOS women are at significantly increased risk for IGT and type 2 diabetes mellitus at all weights and at a young age; 2) these prevalence rates are similar in 2 different populations of PCOS women, suggesting that PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women; and 3) the American Diabetes Association diabetes diagnostic criteria failed to detect a significant number of PCOS women with diabetes by postchallenge glucose values.

A randomized comparison of the methods of sperm preparation for intrauterine insemination.

OBJECTIVE: To compare the effectiveness of three methods of sperm preparation for IUI during superovulation of infertile women. DESIGN: Randomized assignment of one of three sperm preparation methods. SETTING: University infertility practice. PATIENT(S): Infertile couples undergoing superovulation and IUI. INTERVENTION(S): The method of preparation of sperm for IUI during superovulation was assigned randomly to double centrifugation, multiple-tube swim-up, or Percoll density gradient. MAIN OUTCOME MEASURE(S): Total number and percent recovery of motile sperm, percent of recovered sperm with normal morphology, and cycle fecundity. RESULT(S): No method of sperm preparation provided better cycle fecundity than the others despite differences in sperm recovery. CONCLUSION(S): Double centrifugation, multiple-tube swim-up, and Percoll density gradient sperm preparation for IUI yield similar cycle fecundity rates.

Radiation dose from DXA scanning to reproductive tissues of females.

The objective of this study was to use an anatomically arrayed whole-body phantom to measure radiation exposure to the ovaries and uterus during standard dual-energy Xray absorptiometry (DXA) scanning. DXA instrument manufacturers' published entrance skin exposure is about 3 mR (0.77 microC/kg), which is equivalent to the radiation exposure received during a transcontinental plane trip. Nonetheless, since DXA scanning is used more frequently with very young females, the need for pregnancy testing has become an issue that requires attention and formulation of research guidelines. We attached thermoluminescent dosimeters (TLDs) to anatomically arrayed balloon models for ovaries and the uterus, and placed these in the appropriate sites within a small human skeleton along with appropriate amounts of aqueous and fat soft tissue equivalents. Whole-body scanning with a Hologic QDR-2000W was performed 10 times with the pencil beam mode and, using separate TLD detectors, 10 times with the fan beam mode. Overall, the average exposures at skin entrance were 0.89 mR (0.23 microC/kg) with doses for the ovaries of 0.52 mrad (5.2 microgy) and 0.59 mrad (5.9 microgy) for the uterus. These doses are equivalent to 2 d of ambient background radiation in central Pennsylvania or 1 h of flying at 39,000 ft. Although different DXA models by Hologic and DXA instruments by other manufacturers will have different radiation outputs, we believe that these low radiation levels do not require pregnancy testing or questioning of whether the scan subject might be pregnant.

ART in women 40 and over. Is the cost worth it?

OBJECTIVE: To determine the efficacy and cost of assisted reproductive techniques in older women (40 years or older) in comparison to younger women (less than 30 years old). STUDY DESIGN: Retrospective review of records from one university-based infertility practice. RESULTS: Women 40 years or older were significantly less likely to achieve pregnancy with human menopausal gonadotropin (hMG)/intrauterine insemination as compared to women under age 30. The older women were also significantly less likely to achieve pregnancy with in vitro fertilization (IVF). The use of donor oocytes resulted in the highest pregnancy rates in older women. Costs per cycle were similar, however, for both groups. CONCLUSION: Older women will consume an equal amount of medical resources per cycle in infertility treatment as compared to younger women (aged < 30 years). However, older women utilizing assisted reproductive techniques are four to five times less likely to achieve pregnancy than the younger group. This poor prognosis for success in older women adds significantly to the mean cost per pregnancy as compared to younger women. Donor oocytes may be the most cost-effective option for achieving pregnancy in older women.

The quality of human embryo growth is improved when embryos are cultured in groups rather than separately.

OBJECTIVE: To determine the effect of culturing human embryos in groups on cleavage rates, morphology grades, and embryo scores when compared with embryos cultured singly. DESIGN: Prospective. SETTING: The IVF-ET program of the Pennsylvania State University, Department of Obstetrics and Gynecology, Hershey Medical Center, Hershey, Pennsylvania. PATIENTS: Fifty-five infertile women who each had at least five zygotes underwent IVF-ET. INTERVENTIONS: Zygotes from each patient were allocated to be cultured singly and in groups. MAIN OUTCOME MEASURES: Cleavage rate, morphology grade, and embryo score. RESULTS: Grouping embryos significantly enhanced cleavage rates and embryo scores but not morphology grade as compared with embryos grown singly. Additionally, the size of the groups correlated positively with cell number and embryo score but not the morphology grade. CONCLUSION: Culturing human embryos in groups enhances the quality of their growth by increasing the cleavage rates and embryo scores. Because pregnancy rates are improved by transferring embryos with higher embryo scores, coculturing human embryos may be a way of enhancing pregnancy rates.

The prognostic value of serum concentrations of progesterone, estradiol, and luteinizing hormone during superovulation with and without adjunctive leuprolide therapy.

OBJECTIVE: To determine the predictive value of preovulatory serum concentrations of P, E2, and LH for pregnancy achieved with IUI after superovulation with and without adjunctive leuprolide acetate (LA) therapy. DESIGN: Randomized, crossover study of superovulation with and without LA therapy. SETTING: Infertility clinic. PATIENTS: Subfertile patients referred for superovulation and IUI. MAIN OUTCOME MEASURES: Preovulatory serum concentrations of P, E2, and LH on the day of hCG administration; pregnancy. RESULTS: Preovulatory serum concentrations of P, E2, and LH had equivalent predictive value for pregnancy during cycles stimulated without LA therapy. No single parameter was particularly useful in clinical decision making. Threshold P concentrations proposed in other studies as useful in predicting pregnancy did not correlate with cycle fecundity. The predictive value of preovulatory concentrations of P during superovulation with adjunctive LA therapy was significantly worse than P concentrations during superovulation without LA therapy. CONCLUSIONS: Preovulatory serum P, E2, and LH concentrations in superovulation and IUI are not helpful in determining prognosis for pregnancy. The relative utility of predictive parameters may vary for different treatment regimens.

Serum human chorionic gonadotropin concentration for predicting multiple gestation in pregnancies conceived with superovulation and intrauterine insemination.

Assisted reproductive technologies are associated with an increased incidence of multiple gestation. Because they provide precise information on the time of ovulation, those technologies afford an opportunity to analyze the association between multiple gestation and maternal serum human chorionic gonadotropin (hCG) concentrations during early pregnancy. We retrospectively evaluated this association in 76 pregnancies (26 multiple) conceived with superovulation and intrauterine insemination. Using multiple linear regression, we discerned that the number of fetuses surviving the first trimester was directly proportional to the log of the hCG concentrations. The mean + 1 SD for the estimated hCG values of singleton pregnancies was selected a priori as the threshold for detecting multiple pregnancies. This threshold value provided a sensitivity of 73%, specificity of 80% and overall accuracy of 78%. Nine of 11 pregnancies with three or more fetuses had hCG concentrations above the threshold values. Although there is a positive correlation between the number of fetuses surviving the first trimester and the hCG concentration early in pregnancy, the predictive value of the hCG concentration is useful only for excluding most triplet and quadruplet pregnancies.

Adjunctive leuprolide therapy does not improve cycle fecundity in controlled ovarian hyperstimulation and intrauterine insemination of subfertile women.

Problems arising from controlled ovarian hyperstimulation for intrauterine insemination, such as premature luteinization and asynchronous ovarian follicular development, are identical to those encountered with controlled ovarian hyperstimulation for in vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT). It has been suggested that the adjunctive use of GnRH agonists for controlled ovarian hyperstimulation improves the efficiency of GIFT and IVF cycles. We hypothesized that adjunctive use of leuprolide acetate, a GnRH agonist, would have a similarly beneficial effect on cycle quality and cycle fecundity in subfertile women treated with controlled ovarian hyperstimulation and intrauterine insemination. We randomly assigned the first cycle of controlled ovarian hyperstimulation and intrauterine insemination for each of 97 subfertile women to include either human menopausal gonadotropins (hMGs) alone or hMGs following midluteal pre-treatment with leuprolide. If a pregnancy did not occur in the first cycle, the woman was given the other treatment in the second cycle. Although the cycles that included leuprolide required a larger amount of hMGs and more days of stimulation per cycle, the mean estradiol concentrations and numbers of follicles were not different. Despite prevention of premature luteinization with leuprolide, the cycle fecundity was not different between groups (0.11 with adjunctive leuprolide treatment and 0.22 with hMGs alone). We conclude that in unselected subfertile patients, the adjunctive use of leuprolide for controlled ovarian hyperstimulation and intrauterine insemination does not improve cycle fecundity compared with treatment cycles that do not include adjunctive leuprolide therapy.

Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility.

Empirical therapy for subfertility using assisted reproductive technologies recently has gained popularity; however, the cost-effectiveness of these therapies, compared with an untreated control group, has not been established. Similarly, there has been no comparative cost analysis of the utility of controlled ovarian hyperstimulation and IUI in the management of the same condition. Significant PRs in untreated couples with subfertility mandate the design and execution of controlled trials to ascertain the role of controlled ovarian hyperstimulation and IUI in infertility therapy. Various disorders of subfertility have been treated with controlled ovarian hyperstimulation and IUI. The rationale for this therapy is the increase in gamete density at the site of fertilization, as with GIFT and IVF when used for management of the same problems. The live birth rate per initiated cycle and risk of complications are similar to results recently reported for GIFT and IVF. The utility of controlled ovarian hyperstimulation and IUI still remains controversial. When the relatively low direct and indirect costs of controlled ovarian hyperstimulation and IUI are considered, acknowledging the lack of prospective, controlled studies, this procedure appears to be at least as cost-effective as GIFT and IVF.

Relationship of laparoscopic findings to self-report of pelvic pain.

An assessment battery including standardized measures of behavioral and psychosocial factors associated with other chronic pain conditions was administered to 102 women scheduled for laparoscopic surgery. Surgeons who were blinded to the patient's self-reported pain data completed the American Fertility Society classification for endometriosis and adhesions on the basis of observed physical disease. Although American Fertility Society classification scores were significantly related to self-assignment into pain or no-pain groups, the extent of physical disease evaluated by this procedure was not significantly correlated with ratings of pain levels or a number of indexes of impairment. The group of patients with laparoscopically diagnosed pathologic conditions reported higher pain levels and greater interference than the group who reported pain and had negative laparoscopic results; however, some women with observable pathologic conditions reported no pain symptoms.

Effect of age on response to human menopausal gonadotropin stimulation.

Conception rates decline in the latter part of the reproductive years. To examine which ovarian parameters are altered with aging, 486 cycles from 225 ovulatory infertile women undergoing human menopausal gonadotropin (hMG) superovulation and washed intrauterine insemination were analyzed. Infertility factors included endometriosis (68%), unexplained infertility (8.4%), male factor (12.9%), and ovulatory dysfunction (10.7%). Parameters that demonstrated a linear relationship with increasing age included numbers of ampules of hMG required per cycle (r = 0.79; P less than 0.05), days of stimulation (r = 0.73; P less than 0.01), estradiol level at the time of hCG (r = -0.92; P less than 0.0001), number of follicles larger than 15 mm (r = -0.61; P less than 0.05), and rate of rise of estradiol (r = -0.92; P less than 0.0001). These same age-dependent changes were observed in women receiving a standard stimulation protocol (3 ampules hMG beginning on cycle day 2). When standard cycles were limited to the first cycle only, the preovulatory estradiol (r = -0.92; P less than 0.005), slope of estradiol rise (r = -0.92; P less than 0.005), and number of preovulatory follicles (r = -0.92; P less than 0.005) still showed a significant decrease with age. Although the mean estradiol level per preovulatory follicle showed a slight decrease with maternal age, no statistically significant trend was noted. In addition, the cycle day of hCG administration was unaffected by age. With advancing age, there appears to be a decreased ovarian response to an increased amount of stimulation, as measured by steroidogenesis and follicular recruitment; yet the estradiol/follicle remains unaltered, indicating continued health of the follicle. These observations may explain in part the observed decrease in fecundity in older women.

Inhibition of FSH-stimulated cAMP accumulation and progesterone production by mono(2-ethylhexyl) phthalate in rat granulosa cell cultures.

Several phthalate esters are male and female reproductive toxicants in vivo. In the male, mono(2-ethylhexyl) phthalate (MEHP), the active metabolite of di(2-ethylhexyl) phthalate (DEHP), inhibits follicle stimulating hormone (FSH)-stimulated cAMP accumulation in the Sertoli cell in vitro. Since granulosa and Sertoli cells share several structural and functional characteristics, the effect of MEHP on granulosa cell intracellular cAMP accumulation was examined to elucidate a possible mechanism for DEHP reproductive toxicity in females. MEHP (100 microM) reduced FSH-stimulated cAMP accumulation in granulosa cells by 40% after a 24-hr preincubation. Significant inhibition of cAMP accumulation by MEHP occurred by 15 hr and MEHP did not affect the dose of FSH which resulted in half-maximal stimulation. Detailed investigations regarding the mechanism of MEHP inhibition were conducted using cholera toxin, forskolin, and isoproterenol. In contrast to FSH, MEHP did not affect the ability of these compounds to stimulate cAMP accumulation. In addition, a functional endpoint of granulosa cell function, progesterone production, was inhibited in a dose-dependent manner by MEHP. Further experiments will be necessary to determine the significance of these findings to in vivo toxicity, but these experiments describe a specific site of action of MEHP in vitro which may be related to the in vivo female reproductive toxicity of phthalate esters.

The luteal phase in polycystic ovary syndrome during ovulation induction with human menopausal gonadotropin with and without leuprolide acetate.

Little data exist on the effects of adjunctive therapy with leuprolide acetate (LA) in the luteal phase of women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with human menopausal gonadotropin (hMG). Additionally, it is not known whether gonadal steroid concentrations in the luteal phase of induced cycles in PCOS are predictive of pregnancy. In this prospective, randomized study comparing cycles using hMG alone (n = 26) with cycles using hMG with LA (n = 33), no differences were noted between treatment groups in progesterone (P), estradiol (E2), and P:E2 ratios on luteal days 3, 6, and 9. When all treatment cycles were pooled, there were no differences in P, E2, or P:E2 ratios, comparing conception and nonconception cycles. We conclude that adjunctive therapy with LA in PCOS patients undergoing ovulation induction with hMG does not alter the luteal phase concentrations of P, E2, and P:E2. Furthermore, no correlation was found between the serum concentrations of these luteal phase steroids and cycle fecundity.

Utility of fluoroimmunoassay in detecting luteinizing hormone surges in spontaneous and human menopausal gonadotropin-stimulated menstrual cycles.

Luteinizing hormone (LH) levels measured with radioimmunoassay and time-resolved fluoroimmunoassay (FIA) in 274 serum samples correlated highly, with a linear correlation coefficient of 0.934. Through the analysis of serial samples from 43 women undergoing human menopausal gonadotropin stimulation for in vitro fertilization or gamete intrafallopian transfer and seven patients monitored in spontaneous menstrual cycles for receipt of frozen embryos, we demonstrated the utility of FIA in the detection of the LH surge. This LH assay technique, which involves no radioactive isotopes, should facilitate the monitoring of ovulation induction patients in the office/ambulatory setting.

Clinical characteristics of ovulation induction with human menopausal gonadotropins with and without leuprolide acetate in polycystic ovary syndrome.

Ovulation induction in polycystic ovary syndrome (PCOS) with human menopausal gonadotropins (hMG) results in suboptimal cycle fecundity and frequently is complicated by ovarian hyperstimulation. The use of a gonadotropin releasing-hormone agonist (Gn-RH-a) with hMG induction of ovulation may improve the therapeutic outcome. In this prospective, randomized trial, 27 women with PCOS underwent a total of 25 cycles of hMG alone and 33 cycles with adjunctive GnRH-a (leuprolide) treatment. Premature luteinization was seen less frequently in the leuprolide-treated cycles than in cycles treated with hMG alone. There were no differences between the treatments in ovarian sensitivity to hMG. Cycle fecundity was 0.16 for hMG alone cycles, and 0.27 for leuprolide with hMG cycles, which were not statistically different. We conclude that the sensitivity of the PCOS ovary to hMG is not affected by 4 weeks of leuprolide pretreatment.